(1)
Department of Pathology, Sinai Hospital of Baltimore Pathology, Baltimore, MD, USA
Keywords
SquamousUrotheliumHyperplasiaMetaplasiaDysplasiaCarcinoma in situInvasionComplex, or multilayered, epithelia (squamous and urothelial) may progress through a spectrum of changes, from benign hyperplasia and/or metaplasia to inflamed reactive changes, to dysplasia, to carcinoma in situ (CIS) , and to invasive carcinoma (crossing the basement membrane). The progression is not inevitable or consistent, and some lesions will regress. However, true dysplasia is generally regarded as a premalignant condition. Carcinoma in situ is one step from invasive cancer and therefore treated aggressively. Some lesions are easily monitored clinically, such as those in the cervix and oral cavity, and therefore each phase of change can be seen, biopsied, and followed. Others, such as in the nasopharynx, are generally not noticed until they are fairly large and/or symptomatic. This chapter will touch on basic principles that these epithelial layers have in common and introduce some organ systems that are covered in greater detail later in the book.
Approach to the Epithelium: General Principles
On low power (4×), look for the following:
Type of epithelium: Is it squamous, columnar, or ciliated?
Architecture: Is it an exophytic structure, such as a verrucous lesion or a papilloma? Is there downward growth, as in an inverted papilloma or invasive lesion?
Keratinization : Is keratinization present or absent? Hyperkeratosis ? Parakeratosis ? Mounds or church spires of keratin (as in a wart)?
Thickness of the epithelium: Is the epithelium thickened and irregular (hyperplastic) or thin and flat (atrophic)? A markedly thickened epithelium may indicate irritation and hyperplasia but not necessarily dysplasia.
Architectural orderliness: Is there a clear difference between the basal layer and the superficial layer? Are the rows of cells orderly (Figure 4.1)? Are the nuclei lined up, either parallel to the surface or perpendicular to it?
Figure 4.1.
Polarity in an epithelium. In this section of urothelium, although it is thickened relative to normal, all of the nuclei can be seen to be roughly perpendicular to the surface; they “know which way is up.” Plump umbrella cells are visible at the surface (arrow).
General color: What color is it? Although it is hard to compare one slide to another, within a single slide, differences in color can make a dysplastic or inflamed area stand out as dark or blue. Islands of bright pink, on the other hand, may indicate deep keratinization, which is a feature of invasion.
On high power, look for the following:
Architectural orderliness and polarity: Try to find a well-oriented fragment, not a tangential cut. In a benign, even reactive epithelium, all of the nuclei should appear to “know which way is up.”
Mitotic figures: Although a few mitoses near the basal layer are acceptable, mitoses higher in the epithelium are not. As above, a well-oriented fragment is very helpful.
Dyskeratotic cells : Small, intensely pink, shriveled round cells that have detached from their neighbors (Figure 4.2) can be a feature of dysplasia.
Figure 4.2.
Dyskeratotic cells in the epidermis. These cells are essentially mummified; their nuclei are dying, and they have lost their connections to other cells. Their dense pink keratin stands out relative to the neighboring cells (arrow). Note the surface parakeratosis.
Inflammation: Look for neutrophils, plasma cells, and lymphocytes. Keep a high threshold for dysplasia in the setting of intense acute inflammation.
Invasion: Stromal invasion is a sure sign of cancer but is not always obvious. Pseudoepitheliomatous hyperplasia (see “Definitions of Terms”) and tangential sectioning are the main mimickers. Features that suggest true invasion include deep aberrant keratinization (pinking up) and single infiltrating cells with atypical nuclei (Figure 4.3). The basement membrane border should appear ragged and discontinuous in invasion. Well-differentiated squamous cell carcinoma can acquire prominent nuclei (usually not seen in CIS) and mimic reactive nuclei, but it should have the architectural features of invasion.
Figure 4.3.
Invasive squamous cell carcinoma . Irregular nests and spicules of cells invade down into the stroma from the surface (top). Although single infiltrating cells are not visible at this magnification, the deep aberrant keratinization (arrow), in which a deep nest of cells takes on the color and texture of the normal surface keratin, is highly suspicious for invasion.
Nuclear Changes: It’s All About the Nucleus, Remember?
Nuclei, eggs versus boulders (Figure 4.4): Reactive nuclei may enlarge but stay smooth and round to oval, and their chromatin condenses into several small nucleoli or speckles, like a bird’s egg. The chromatin may have an overall grey-blue look, and the nuclear membrane is often indistinct. Dysplastic or immature nuclei, however, appear to have too much chromatin. They are large and tend to be angulated with irregular nuclear membranes (like boulders), and the chromatin is uniformly dense and dark, like it was drawn with charcoal. Nuclear membranes may also appear thicker and more prominent.
Figure 4.4.
Examples of reactive, benign nuclei (a, b) and dysplastic nuclei (c, d). In reactive conditions (upper panels), the nuclei may be enlarged and have visible nucleoli, but the N/C ratios are still low (abundant cytoplasm), there is nuclear polarity relative to the surface, the chromatin is not too dark, and the nuclear membranes are smooth and oval. Maturation is visible in that as cells get closer to the surface, the nuclei get smaller and the cytoplasm more abundant. In dysplasia (lower panels), the nuclei are significantly darker, the N/C ratios are higher, there is more disorder to the epithelium, and the nuclei (being more closely packed) may take on irregular shapes to fit more closely together, similar to boulders in a rock wall.
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